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EP3923940B1 - Combinaison pharmaceutique comprenant du tno155 et un inhibiteur de pd-1 - Google Patents

Combinaison pharmaceutique comprenant du tno155 et un inhibiteur de pd-1

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Publication number
EP3923940B1
EP3923940B1 EP20707826.2A EP20707826A EP3923940B1 EP 3923940 B1 EP3923940 B1 EP 3923940B1 EP 20707826 A EP20707826 A EP 20707826A EP 3923940 B1 EP3923940 B1 EP 3923940B1
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EP
European Patent Office
Prior art keywords
tno155
cancer
use according
pharmaceutically acceptable
acceptable salt
Prior art date
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Active
Application number
EP20707826.2A
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German (de)
English (en)
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EP3923940A1 (fr
Inventor
Ying-Nan Pan Chen
Huaixiang Hao
Chen Liu
Morvarid MOHSENI
William D. HASTINGS
Silvia GOLDONI
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Novartis AG
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Novartis AG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/58—Medicinal preparations containing antigens or antibodies raising an immune response against a target which is not the antigen used for immunisation
    • A61K2039/585—Medicinal preparations containing antigens or antibodies raising an immune response against a target which is not the antigen used for immunisation wherein the target is cancer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered

Definitions

  • the present invention relates to a pharmaceutical combination comprising TNO155 and a PD-1 inhibitor; such combinations for use in the treatment of cancers.
  • TNO155 is an orally bioavailable, allosteric inhibitor of Src homology-2 domain containing protein tyrosine phsophatase-2 (SHP2, encoded by the PTPN11 gene), which transduces signals from activated receptor tyrosine kinases (RTKs) to downstream pathways, including the mitogen-activated protein kinase (MAPK) pathway.
  • SHP2 has also been implicated in immune checkpoint and cytokine receptor signaling.
  • TNO155 has demonstrated efficacy in a wide range of RTK-dependent human cancer cell lines and in vivo tumor xenografts.
  • the Programmed Death 1 (PD-1) protein is an inhibitory member of the extended CD28/CTLA-4 family of T cell regulators.
  • Two ligands for PD-1 have been identified, PD-L1 (B7-H1) and PD-L2 (B7-DC), that have been shown to downregulate T cell activation upon binding to PD-1.
  • PD-L1 is abundant in a variety of human cancers.
  • PD-1 is known as an immunoinhibitory protein that negatively regulates TCR signals.
  • the interaction between PD-1 and PD-L1 can act as an immune checkpoint, which can lead to, for example, a decrease in tumor infiltrating lymphocytes, a decrease in T-cell receptor mediated proliferation, and/or immune evasion by cancerous cells.
  • Immune suppression can be reversed by inhibiting the local interaction of PD-1 with PD-L1 or PD-L2; the effect is additive when the interaction of PD-1 with PD-L2 is blocked as well.
  • WO2018/130928 discusses the use of the SHP2 inhibitor TNO155 in the treatment of cancer in combination with an ALK inhibitor.
  • the present invention provides for a pharmaceutical combination comprising:
  • the immune checkpoint inhibitor is a PD-1 inhibitor.
  • the PD-1 inhibitor is chosen from PDR001 (spartalizumab; Novartis), Nivolumab (Bristol-Myers Squibb), Pembrolizumab (Merck & Co), Pidilizumab (CureTech), MEDI0680 (Medimmune), REGN2810 (Regeneron), TSR-042 (Tesaro), PF-06801591 (Pfizer), BGB-A317 (Beigene), BGB-108 (Beigene), INCSHR1210 (Incyte), or AMP-224 (Amplimmune).
  • the PD-1 inhibitor is PDR001 (spartalizumab).
  • the PD-1 inhibitor is administered at a dose of about 300-400 mg.
  • the PD-1 inhibitor is administered once every 3 weeks or once every 4 weeks.
  • the PD-1 inhibitor is administered at a dose of about 300 mg once every 3 weeks.
  • the PD-1 inhibitor is administered at a dose of about 400 mg once every 4 weeks.
  • Combinations of TNO155, or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitior e.g. a PD-1 inhibitor
  • an immune checkpoint inhibitior e.g. a PD-1 inhibitor
  • TNO155 or a pharmaceutically acceptable salt thereof and a PD-1 inhibitor are in separate formulations.
  • the combination of the invention is for simultaneous or sequential (in any order) administration.
  • an immune checkpoint inhibitor for use in the treatment of cance,r wherein the treatment further comprises administration of (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (TNO155), or a pharmaceutically acceptable salt thereof.
  • the cancer is selected from: esophageal or head and neck squamous cell carcinoma; colorectal, ovarian, pancreatic or non-small cell lung cancer; and renal cell carcinoma.
  • the cancer is colorectal cancer.
  • the cancer is non-small cell lung cancer.
  • the cancer is head and neck squamous cell carcinoma.
  • composition comprising the combination of the invention.
  • the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients as described herein.
  • subject or “patient” as used herein is intended to include animals, which are capable of suffering from or afflicted with a cancer or any disorder involving, directly or indirectly, a cancer.
  • subjects include mammals, e.g., humans, apes, monkeys, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals.
  • the subject is a human, e.g., a human suffering from, at risk of suffering from, or potentially capable of suffering from cancers.
  • treating comprises a treatment relieving, reducing or alleviating at least one symptom in a subject or effecting a delay of progression of a disease.
  • treatment can be the diminishment of one or several symptoms of a disorder or partial or complete eradication of a disorder, such as cancer.
  • the term “treat” also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease.
  • composition therapy refers to the administration of two or more therapeutic agents to treat a condition or disorder described in the present disclosure (e.g., cancer).
  • administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients.
  • administration encompasses co-administration in multiple, or in separate containers ( e.g., capsules, powders, and liquids) for each active ingredient. Powders and/or liquids may be reconstituted or diluted to a desired dose prior to administration.
  • administration also encompasses use of each type of therapeutic agent in a sequential manner, either at approximately the same time or at different times. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.
  • the combination therapy can provide "synergy” and prove “synergistic", i.e., the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately.
  • a synergistic effect can be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined, unit dosage formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen.
  • alternation therapy a synergistic effect can be attained when the compounds are administered or delivered sequentially, e.g., by different injections in separate syringes.
  • synergistic effect refers to action of two therapeutic agents such as, for example, a compound TNO155 as a SHP2 inhibitor and a PD-1 inhibitor, producing an effect, for example, slowing the symptomatic progression of a proliferative disease, particularly cancer, or symptoms thereof, which is greater than the simple addition of the effects of each drug administered by themselves.
  • a synergistic effect can be calculated, for example, using suitable methods such as the Sigmoid-Emax equation ( Holford, N. H. G. and Scheiner, L. B., Clin.
  • pharmaceutical combination refers to either a fixed combination in one dosage unit form, or non-fixed combination or a kit of parts for the combined administration where two or more therapeutic agents may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g. synergistic effect.
  • PD-1 inhibitors include PDR001.
  • PDR001 is also known as spartalizumab, an anti-PD-1 antibody molecule described in US 2015/0210769, published on July 30, 2015 , entitled “Antibody Molecules to PD-1 and Uses Thereof”.
  • anti-PD-1 antibody molecules include the following:
  • a combination of the invention, TNO155 and a PD-1 inhibitor is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
  • Isotopically labeled compounds have one or more atoms replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into TNO155 and a PD-1 inhibitor include isotopes, where possible, of hydrogen, carbon, nitrogen, oxygen, and chlorine, for example, 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 35 S, 36 Cl.
  • the invention includes isotopically labeled TNO155 and a PD-1 inhibitor, for example into which radioactive isotopes, such as 3 H and 14 C, or nonradioactive isotopes, such as 2 H and 13 C, are present.
  • Isotopically labelled TNO155 and a PD-1 inhibitor are useful in metabolic studies (with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using appropriate isotopically-labeled reagents.
  • isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a substituent in TNO155 or a PD-1 inhibitor is denoted deuterium
  • such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine, or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor, or a pharmaceutically acceptable salt thereof, are administered separately, simultaneously or sequentially, in any order.
  • (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine is in an oral dose form.
  • composition comprising a pharmaceutical combination of (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine, or pharmaceutically acceptable salt thereof, and a PD-1 inhibitor and at least one pharmaceutically acceptable carrier.
  • the PD-1 inhibitor is an anti-PD-1 antibody molecule.
  • the PD-1 inhibitor is an anti-PD-1 antibody molecule as described in US 2015/0210769, published on July 30, 2015 , entitled "Antibody Molecules to PD-1 and Uses Thereof".
  • the anti-PD-1 antibody molecule is BAP049-Clone E or BAP049-Clone B.
  • the anti-PD-1 antibody molecule is Spartalizumab (PDR001).
  • the anti-PD-1 antibody molecule comprises at least one, two, three, four, five or six complementarity determining regions (CDRs) (or collectively all of the CDRs) from a heavy and light chain variable region comprising an amino acid sequence shown in Table 1 ( e.g ., from the heavy and light chain variable region sequences of BAP049-Clone-E or BAP049-Clone-B disclosed in Table 1), or encoded by a nucleotide sequence shown in Table 1.
  • the CDRs are according to the Kabat definition ( e.g ., as set out in Table 1).
  • the CDRs are according to the Chothia definition ( e.g ., as set out in Table 1).
  • the CDRs are according to the combined CDR definitions of both Kabat and Chothia (e.g ., as set out in Table 1).
  • the combination of Kabat and Chothia CDR of VH CDR1 comprises the amino acid sequence GYTFTTYWMH (SEQ ID NO: 541).
  • one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, relative to an amino acid sequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1.
  • the anti-PD-1 antibody molecule comprises a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 501, a VHCDR2 amino acid sequence of SEQ ID NO: 502, and a VHCDR3 amino acid sequence of SEQ ID NO: 503; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 510, a VLCDR2 amino acid sequence of SEQ ID NO: 511, and a VLCDR3 amino acid sequence of SEQ ID NO: 512, each disclosed in Table 1.
  • VH heavy chain variable region
  • VL light chain variable region
  • the antibody molecule comprises a VH comprising a VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 524, a VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 525, and a VHCDR3 encoded by the nucleotide sequence of SEQ ID NO: 526; and a VL comprising a VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 529, a VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 530, and a VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 531, each disclosed in Table 1.
  • the anti-PD-1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 506, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 506. In one embodiment, the anti-PD-1 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 520, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 520. In one embodiment, the anti-PD-1 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 516, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 516.
  • the anti-PD-1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 506 and a VL comprising the amino acid sequence of SEQ ID NO: 520. In one embodiment, the anti-PD-1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 506 and a VL comprising the amino acid sequence of SEQ ID NO: 516.
  • the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 507, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 507. In one embodiment, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 521 or 517, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 521 or 517. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 507 and a VL encoded by the nucleotide sequence of SEQ ID NO: 521 or 517.
  • the anti-PD-1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 508, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 508. In one embodiment, the anti-PD-1 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 522, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 522. In one embodiment, the anti-PD-1 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 518, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 518.
  • the anti-PD-1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 508 and a light chain comprising the amino acid sequence of SEQ ID NO: 522. In one embodiment, the anti-PD-1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 508 and a light chain comprising the amino acid sequence of SEQ ID NO: 518.
  • the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 509, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 509.
  • the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 523 or 519, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 523 or 519.
  • the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 509 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 523 or 519.
  • the antibody molecules described herein can be made by vectors, host cells, and methods described in US 2015/0210769 .
  • Table 1 Amino acid and nucleotide sequences of exemplary anti-PD-1 antibody molecules BAP049-Clone-B HC SEQ ID NO: 501 (Kabat) HCDR1 TYWMH SEQ ID NO: 502 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 503 (Kabat) HCDR3 WTTGTGAY SEQ ID NO: 504 (Chothia) HCDR1 GYTFTTY SEQ ID NO: 505 (Chothia) HCDR2 YPGTGG SEQ ID NO: 503 (Chothia) HCDR3 WTTGTGAY SEQ ID NO: 506 VH SEQ ID NO: 507 DNA VH SEQ ID NO: 508 Heavy chain SEQ ID NO: 509 DNA heavy chain BAP049-Clone-B LC SEQ ID NO
  • the cancer is selected from esophageal squamous cell carcinoma, head and neck squamous cell carcinoma, colorectal cancer, ovarian cancer, pancreatic cancer, non-small cell lung cancer and renal cell carcinoma.
  • the cancer is selected from esophageal squamous cell carcinoma and pharyngeal squamous cell carcinoma.
  • the cancer is colorectal cancer.
  • the cancer is non-small cell lung cancer.
  • the cancer is head and neck squamous cell carcinoma.
  • (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine, or pharmaceutically acceptable salt thereof, and the second therapeutic agent are administered simultaneously, separately or over a period of time.
  • the amount of (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine, or pharmaceutically acceptable salt thereof, administered to the subject in need therof is effective to treat the cancer.
  • the amounts of (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine, or pharmaceutically acceptable salt thereof, and the second therapeutic agent, administered to the subject in need thereof is effective to treat the cancer.
  • the second therapeutic agent is an immunomodulator.
  • the second therapeutic agent is an immune checkpoint inhibitor.
  • the second therapeutic agent is a PD-1 inhibitor.
  • the PD-1 inhibitor is selected from PDR001, Nivolumab, Pembrolizumab, Pidilizumab, MEDI0680, REGN2810, TSR-042, PF-06801591, BGB-A317, BGB-108, INCSHR1210, or AMP-224.
  • the PD-1 inhibitor is PDR001.
  • (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine, or pharmaceutically acceptable salt thereof is administered orally at a dose of about 1.5 mg per day, or 3 mg per day, or 6 mg per day, or 10 mg per day, or 20 mg per day, or 30 mg per day, or 40 mg per day, or 50 mg per day, or 60 mg per day, or 70 mg per day, or 80 mg per day, or 90 mg per day, or 100 mg per day.
  • the dose per day of (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine, or pharmaceutically acceptable salt thereof is on a 21 day cycle of 2 weeks on drug followed by 1 week off drug.
  • the dose is 20 mg QD per day of (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine, or pharmaceutically acceptable salt thereof, is on a 21 day cycle of 2 weeks on drug followed by 1 week off drug.
  • PDR001 is administered at a dose of about 300 mg once every 3 weeks.
  • PDR001 is administered at a dose of about 400 mg once every 4 weeks.
  • the dose per day of (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine, or pharmaceutically acceptable salt thereof is on a 21 day cycle of 2 weeks on drug followed by 1 week off drug.
  • the dose is 20 mg QD per day of (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine, or pharmaceutically acceptable salt thereof, is on a 21 day cycle of 2 weeks on drug followed by 1 week off drug.
  • the cancer is selected from esophageal squamous cell carcinoma, head and neck squamous cell carcinoma, colorectal cancer, ovarian cancer, pancreatic cancer, non-small cell lung cancer and renal cell carcinoma.
  • the cancer is colorectal cancer.
  • the cancer is non-small cell lung cancer.
  • the cancer is head and neck squamous cell carcinoma.
  • (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine, or pharmaceutically acceptable salt thereof, and the second therapeutic agent are administered simultaneously, separately, or over a period of time.
  • the second therapeutic agent is an immunomodulator.
  • the second therapeutic agent is an immune checkpoint inhibitor.
  • the second therapeutic agent is a PD-1 inhibitor.
  • the PD-1 inhibitor is selected from PDR001, Nivolumab, Pembrolizumab, Pidilizumab, MEDI0680, REGN2810, TSR-042, PF-06801591, BGB-A317, BGB-108, INCSHR1210, or AMP-224.
  • the PD-1 inhibitor is PDR001.
  • PDR001 is administered at a dose of about 300 mg once every 3 weeks.
  • PDR001 is administered at a dose of about 400 mg once every 4 weeks.
  • the second therapeutic agent is administered intravenously.
  • the cancer is colorectal cancer.
  • the cancer is non-small cell lung cancer.
  • the cancer is head and neck squamous cell carcinoma.
  • the cancer is selected from: esophageal or head and neck squamous cell carcinoma; colorectal, ovarian, pancreatic or non-small cell lung cancer; and and the immune checkpoint inhibitor is PDR001
  • Non-small cell lung cancer In 2012, approximately 1.8 million people worldwide were diagnosed with lung cancer, and an estimated 1.6 million people died from the disease.
  • Non-small cell lung cancer comprises approximately 85% of lung cancers, with adenocarcinomas and squamous cell carcinomas being the most common subtypes.
  • Standard of care treatment for advanced stage non-small cell lung carcinomas (NSCLCs) that do not harbor genetic alterations in druggable driver oncogenes such as EGFR, ALK, or ROS includes chemotherapy and immunotherapy, administered concurrently or sequentially. While these treatments provide clinical benefit, the majority of patients experience disease progression within a year, and the prognosis for patients with advanced NSCLC remains poor.
  • Head and neck squamous cell cancer - Squamous cell cancers are the most common cancers occurring in the head and neck, with an estimated worldwide incidence of approximately 686,000 for oropharyngeal and laryngeal cancers combined. Alcohol and tobacco use are the most common risk factors for head and neck squamous cell cancers (HNSCCs), with human papilloma virus (HPV) infection likely also playing a causative role. More than 90% of HNSCCs have overexpression of EGFR or its ligands. For patients with metastatic disease, standard systemic treatment includes platinum-based chemotherapy with or without cetuximab. Historically, median survival with systemic chemotherapy is approximately six months, with only approximately 20% of patients surviving one year.
  • nivolumab an anti-programmed death-1 (PD-1) antibody
  • standard second-line single agent therapy docetaxel, methotrexate, or cetuximab
  • Colorectal cancer - Colorectal cancer is the second most common cancer in women and the third most common cancer in men, accounting for an estimated 1.4 million new cancer cases worldwide in 2012.
  • Chromosomal instability and microsatellite instability both play roles in the pathogenesis of CRC.
  • Chromosomal instability is found in approximately 85% of sporadic colorectal cancers and is characterized by mutations in the Wnt pathway genes, APC and CTNNB1.
  • KRAS mutations, occurring most commonly in codon 12 or 13 are present in approximately 45% of these cases and render anti-EGFR therapies ineffective.
  • MSI Microsatellite instability
  • Systemic therapy for metastatic CRC includes various agents used alone or in combination, including chemotherapies such as 5-Fluorouracil/leucovorin, capecitabine, oxaliplatin, and irinotecan; anti-angiogenic agents such as bevacizumab and ramucirumab; anti-EGFR agents including cetuximab and panitumumab for KRAS/NRAS wild-type cancers; and immunotherapies including nivolumab and pembrolizumab.
  • chemotherapies such as 5-Fluorouracil/leucovorin, capecitabine, oxaliplatin, and irinotecan
  • anti-angiogenic agents such as bevacizumab and ramucirumab
  • anti-EGFR agents including cetuximab and panitumumab for KRAS/NRAS wild-type cancers
  • immunotherapies including nivolumab and pembrolizumab.
  • TNO155 is a first-in-class allosteric inhibitor of wild-type SHP2.
  • SHP2 is a ubiquitously expressed non-receptor protein tyrosine phosphatase (PTP) composed of two N-terminal SH2 domains, a classic PTP domain, and a C-terminal tail. The phosphatase activity is auto-inhibited by the two SHP2 domains that bind to the PTP domain (closed conformation).
  • PTP non-receptor protein tyrosine phosphatase
  • RTKs receptor tyrosine kinases
  • SHP2 Upon activation of receptor tyrosine kinases (RTKs), SHP2 is recruited to the plasma membrane where it associates with activated RTKs and a number of adaptor proteins to relay signaling by activating the RAS/MAPK pathway.
  • TNO155 binds the inactive, or "closed" conformation of SHP2, thereby preventing its opening into the active conformation.
  • TNO155 has demonstrated efficacy in a wide range of RTK-dependent human cancer cell lines and in vivo xenografts.
  • Preclinical in vitro and in vivo evaluation of TNO155 demonstrate selective and potent inhibition of the SHP2 phosphatase, in RTK-dependent human cancer models, for example, esophageal, HNSCC and NSCLC.
  • SHP2 inhibition can be measured by assessing biomarkers within the MAPK signaling pathway, such as decreased levels of phosphorylated ERK1/2 (pERK) and downregulation of dual specificity phosphatase 6 (DUSP6) mRNA transcript.
  • pERK phosphorylated ERK1/2
  • DUSP6 dual specificity phosphatase 6
  • the in vitro pERK IC50's were 8 nM (3.4 ng/mL) and 35 nM (14.8 ng/mL) and the antiproliferation IC50's were 100 nM (42.2 ng/mL) and 470 nM (198.3 ng/mL), respectively.
  • the antiproliferative effect of TNO155 was revealed to be most effective in cancer cell lines that are dependent on RTK signaling.
  • SHP2 inhibition by orally-administered TNO155 (20 mg/kg) achieved approximately 95% decrease in DUSP6 mRNA transcript in an EGFR-dependent DETROIT-562 cancer cell line and 47% regression when dosed on a twice-daily schedule.
  • Dose fractionation studies, coupled with modulation of the tumor DUSP6 biomarker show that maximal efficacy is achieved when 50% PD inhibition is attained for at least 80% of the dosing interval.
  • SHP2 is implicated in immune checkpoint and cytokine receptor signaling.
  • SHP2 was shown to be recruited by Programmed cell death-1 (PD-1) to dephosphorylate and inactivate the co-stimulatory receptor CD28, which suppresses T cell activation.
  • PD-1 Programmed cell death-1
  • SHP2 ablation in myeloid cells inhibited melanoma growth by potentiating production of the T-cell chemoattractant CXCL9 by macrophages in response to IFN- ⁇ and tumor cell-derived cytokines, thereby facilitating tumor infiltration of IFN- ⁇ -producing T cells.
  • SHP2 may achieve anti-tumor efficacy through multiple mechanisms including direct inhibition of cancer cell growth, activation of tumor targeting T cells, and promotion of T cell tumor infiltration.
  • SHP2 is implicated in PD-1 suppression of T-cell activation and the immune signaling in other immune-suppressive cells such as type 2 tumor associated macrophages (TAM).
  • TAM tumor associated macrophages
  • the immune system is tightly controlled by a network of costimulatory and co-inhibitory ligands and receptors. These molecules provide the second signal for T cell activation and provide a balanced network of positive and negative signals to maximize immune responses against infection, while limiting immunity to self.
  • costimulatory signals include the binding between the B7.1 (CD80) and B7.2 (CD86) ligands of the APC and the CD28 and CTLA-4 receptors of the CD4 + T-lymphocyte. Binding of B7.1 or B7.2 to CD28 stimulates T cell activation, whereas binding of B7.1 or B7.2 to CTLA-4 inhibits such activation.
  • CD28 is constitutively expressed on the surface of T cells, whereas CTLA4 expression is rapidly up-regulated following T-cell activation.
  • B7 Superfamily a group of related B7 molecules, also known as the "B7 Superfamily”.
  • B7 Superfamily Several members of the B7 Superfamily are known, including B7.1 (CD80), B7.2 (CD86), the inducible co-stimulator ligand (ICOS-L), the programmed death-1 ligand (PD-L1; B7-H1), the programmed death-2 ligand (PD-L2; B7-DC), B7-H3, B7-H4 and B7-H6.
  • the Programmed Death 1 (PD-1) protein is an inhibitory member of the extended CD28/CTLA-4 family of T cell regulators.
  • Two ligands for PD-1 have been identified, PD-L1 (B7-H1) and PD-L2 (B7-DC), that have been shown to downregulate T cell activation upon binding to PD-1.
  • PD-L1 is abundant in a variety of human cancers.
  • PD-1 is known as an immunoinhibitory protein that negatively regulates TCR signals.
  • the interaction between PD-1 and PD-L1 can act as an immune checkpoint, which can lead to, e.g., a decrease in tumor infiltrating lymphocytes, a decrease in T-cell receptor mediated proliferation, and/or immune evasion by cancerous cells.
  • Immune suppression can be reversed by inhibiting the local interaction of PD-1 with PD-L1 or PD-L2; the effect is additive when the interaction of PD-1 with PD-L2 is blocked as well.
  • PDR001 (spartalizumab) binds specifically and with high affinity to human PD-1.
  • KD constant of dissociation
  • spartalizumab enhances IL-2 production by approximately 2-fold in response to super antigen stimulation with Staphylococcal enterotoxin B (SEB).
  • SEB Staphylococcal enterotoxin B
  • TNO155 is a potent inhibitor of wild-type SHP2, which enhances the anti-tumor activity of immune checkpoint inhibitors.
  • Preclinical mouse syngeneic tumor model studies have demonstrated enhanced anti-tumor activity of an anti-PD-1 antibody when combined with TNO155.
  • TNO155 has demonstrated single agent activity in preclinical NSCLC and HNSCC models, and anti-PD-1 agents have demonstrated clinical efficacy in subsets of NSCLC and HNSCC patients.
  • a combination of the present invention, TNO155 and PDR001 shows improved efficacy compared to either single agent alone in the treatment of a syngeneic MC38 CRC tumor-bearing immune-competent mouse model.
  • the combinations disclosed herein can result in one or more of: an increase in antigen presentation, an increase in effector cell function (e.g., one or more of T cell proliferation, IFN-y secretion or cytolytic function), inhibition of regulatory T cell function, an effect on the activity of multiple cell types (e.g., regulatory T cell, effector T cells and NK cells), an increase in tumor infiltrating lymphocytes, an increase in T-cell receptor mediated proliferation, a decrease in immune evasion by cancerous cells, and a decrease in oncogenic activity (e.g., overexpression of an oncogene).
  • an increase in antigen presentation an increase in effector cell function (e.g., one or more of T cell proliferation, IFN-y secretion or cytolytic function), inhibition of regulatory T cell function, an effect on the activity of multiple cell types (e.g., regulatory T cell, effector T cells and NK cells), an increase in tumor infiltrating lymphocytes, an increase in T-cell receptor mediated proliferation, a decrease in immune
  • the use of a PD-1 inhibitor in the combinations inhibits, reduces or neutralizes one or more activities of PD-1, resulting in blockade or reduction of an immune checkpoint.
  • a PD-1 inhibitor in the combinations inhibits, reduces or neutralizes one or more activities of PD-1, resulting in blockade or reduction of an immune checkpoint.
  • the cancer treated with the combination includes but is not limited to, a solid tumor, a hematological cancer (e.g., leukemia, lymphoma, myeloma, e.g., multiple myeloma), and a metastatic lesion.
  • a hematological cancer e.g., leukemia, lymphoma, myeloma, e.g., multiple myeloma
  • a metastatic lesion e.g., leukemia, lymphoma, myeloma, e.g., multiple myeloma
  • the cancer is a solid tumor.
  • solid tumors include malignancies, e.g., sarcomas and carcinomas, e.g., adenocarcinomas of the various organ systems, such as those affecting the lung, breast, ovarian, lymphoid, gastrointestinal (e.g., colon), anal, genitals and genitourinary tract (e.g., renal, urothelial, bladder cells, prostate), pharynx, CNS (e.g., brain, neural or glial cells), head and neck, skin (e.g., melanoma), and pancreas, as well as adenocarcinomas which include malignancies such as colon cancers, rectal cancer, renal cancer (e.g., renal-cell carcinoma (clear cell or non-clear cell renal cell carcinoma), liver cancer, lung cancer (e.g., non-small cell lung cancer (squamous or non-squamous non-small cell lung cancer)), cancer of the small intestine and cancer of the e
  • the cancer is an advanced cancer. In some embodiments, the cancer is a metastatic cancer. In some embodiments, the cancer is a relapsed cancer. In some embodiments, the cancer is a refractory cancer. In some embodiments, the cancer is a recurrent cancer. In some embodiments, the cancer is an unresectable cancer.
  • the cancer is a microsatellite instability-high (MSI-H) cancer. In some embodiments, the cancer is a mismatch repair deficient (dMMR) cancer.
  • MSI-H microsatellite instability-high
  • dMMR mismatch repair deficient
  • the cancer e.g., cancer cells, cancer microenvironment, or both
  • the cancer has an elevated level of PD-L1 expression.
  • the cancer e.g., cancer cells, cancer microenvironment, or both
  • the subject has, or is identified as having, a cancer that has one or more of high PD-L1 level or expression, or as being tumor infiltrating lymphocyte (TIL)+ (e.g., as having an increased number of TILs), or both.
  • TIL tumor infiltrating lymphocyte
  • the subject has, or is identified as having, a cancer that has high PD-L1 level or expression and that is TIL+.
  • the subject is identified based on having a cancer that has one or more of high PD-L1 level or expression, or as being TIL+, or both.
  • the subject is identified based on having a cancer that has high PD-L1 level or expression and as being TIL+.
  • a cancer that is TIL+ is positive for CD8 and IFN ⁇ .
  • the subject has, or is identified as having, a high percentage of cells that are positive for one, two or more of PD-L1, CD8, or IFN ⁇ .
  • the subject has, or is identified as having, a high percentage of cells that are positive for all of PD-L1, CD8, and IFN ⁇ .
  • the subject is identified based on having a high percentage of cells that are positive for one, two or more of PD-L1, CD8, and/or IFN ⁇ . In certain embodiments, the subject is identified based on having a high percentage of cells that are positive for all of PD-L1, CD8, and IFN ⁇ .
  • the subject has, or is identified as having, one, two or more of PD-L1, CD8, and/or IFN ⁇ , and one or more of , esophageal cancer, an ovarian cancer, a breast cancer, a pancreatic cancer, a colorectal cancer, a skin cancer, a gastric cancer, an ER+ cancer, a head and neck squamous cell carcinoma, or a renal cell carcinoma.
  • the subject is identified based on having one, two or more of PD-L1, CD8, and/or IFN ⁇ , and one or more of a breast cancer, a pancreatic cancer, a colorectal cancer, a skin cancer, a gastric cancer, or an ER+ cancer).
  • Methods and compositions disclosed herein are useful for treating metastatic lesions associated with the aforementioned cancers.
  • the combinations as described herein can be administered to the subject systemically (e.g., orally, parenterally, subcutaneously, intravenously, rectally, intramuscularly, intraperitoneally, intranasally, transdermally, or by inhalation or intracavitary installation), topically, or by application to mucous membranes, such as the nose, throat and bronchial tubes.
  • the PD-1 inhibitor is administered by injection (e.g., subcutaneously or intravenously) at a dose (e.g., a flat dose) of about 100 mg to 600 mg, e.g., about 200 mg to 500 mg, e.g., about 250 mg to 450 mg, about 300 mg to 400 mg, about 250 mg to 350 mg, about 350 mg to 450 mg, or about 100 mg, about 200 mg, about 300 mg, or about 400 mg.
  • the dosing schedule (e.g., flat dosing schedule) can vary from e.g., once a week to once every 2, 3, 4, 5, or 6 weeks.
  • the PD-1 inhibitor is administered at a dose from about 300 mg to 400 mg once every three weeks or once every four weeks. In one embodiment, the PD-1 inhibitor is administered at a dose from about 300 mg once every three weeks. In one embodiment, the PD-1 inhibitor is administered at a dose from about 400 mg once every four weeks. In one embodiment, the PD-1 inhibitor is administered at a dose from about 300 mg once every four weeks. In one embodiment, the PD-1 inhibitor is administered at a dose from about 400 mg once every three weeks.
  • the epidermal growth factor receptor is an established critical therapeutic target in NSCLCs harboring activating EGFR mutations.
  • Numerous trials with first (e.g. erlotinib, gefitinib) and second (e.g. afatinib, dacomitinib) generation EGFR inhibitors have been conducted in the EGFR-mutant advanced/unresectable NSCLC population, and have consistently demonstrated superior efficacy of EGFR tyrosine kinase inhibitors (TKIs) over chemotherapy in this population.
  • first (e.g. erlotinib, gefitinib) and second (e.g. afatinib, dacomitinib) generation EGFR inhibitors have been conducted in the EGFR-mutant advanced/unresectable NSCLC population, and have consistently demonstrated superior efficacy of EGFR tyrosine kinase inhibitors (TKIs) over chemotherapy in this population.
  • TKIs EGFR ty
  • More than 90% of head and neck cancers are characterized by overexpression or amplification of EGFR ; amplification/overexpression of other RTKs, particularly FGFRs, and their ligands is also common. Inhibition of EGFR with cetuximab in advanced HNSCCs has also demonstrated clinical benefit, though disease control is not durable.
  • the modest efficacy of EGFR inhibition in HNSCC may be related to compensatory signaling through other RTKs, which would be predicted to be abrogated by SHP2 inhibition with TNO155 treatment.
  • preclinical testing identified head and neck cancer cells as the lineage with the highest frequency of sensitivity to SHP2 inhibition.
  • RTK-driven cancers such as anaplastic lymphoma kinase ( ALK )-rearranged NSCLC or stem cell factor receptor ( KIT )-mutant gastrointestinal stromal tumor (GIST) derive benefit from molecules directly targeting these RTKs, but resistance to these agents invariably occurs. Mechanisms of resistance frequently include drug-resistant mutations in the targeted RTK and/or activation of bypass RTK pathways; in most cases, further treatment options are limited. Targeting SHP2 with TNO155 is a rational approach in such RTK-dependent cancers.
  • ALK anaplastic lymphoma kinase
  • KIT stem cell factor receptor
  • GIST gastrointestinal stromal tumor
  • the present invention provides pharmaceutically acceptable compositions which comprise a therapeutically-effective amount TNO155 and a PD-1 inhibitor, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • the pharmaceutical compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue.
  • terapéuticaally-effective amount means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells in an animal at a reasonable benefit/risk ratio applicable to any medical treatment.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically-acceptable carrier means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • manufacturing aid e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid
  • solvent encapsulating material involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydrox
  • certain embodiments of the present compounds may contain a basic functional group, such as amino or alkylamino, and are, thus, capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable acids.
  • pharmaceutically-acceptable salts refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed during subsequent purification.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19 ).
  • the pharmaceutically acceptable salts of the subject compounds include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from non-toxic organic or inorganic acids.
  • such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.
  • the pharmaceutically acceptable salt of TNO155 for example, is succ
  • the compounds of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable bases.
  • pharmaceutically-acceptable salts refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine.
  • a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. (See, for example, Berge et al., supra )
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
  • Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 0.1 per cent to about ninety-nine percent of active ingredient, preferably from about 5 per cent to about 70 per cent, most preferably from about 10 percent to about 30 percent.
  • a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present invention.
  • an aforementioned formulation renders orally bioavailable a compound of the present invention.
  • Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution, suspension or solid dispersion in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • a compound of the present invention may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as poloxa
  • pharmaceutically-acceptable carriers such as sodium citrate or dicalcium phosphate
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions.
  • the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • the compounds of the present invention which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of the combination of the invention will be that amount of each compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • the present invention provides pharmaceutically acceptable compositions which comprise a therapeutically-effective amount of one or more of the subject compounds, as described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • TNO155 and PDR001 described herein can be evidenced by testing in the following examples.
  • TNO155 had no impact on downstream MAPK-signaling markers in tumor cells, such as phospho-ERK and phospho-RSK.
  • Phenotypic markers are shown (see Figure 2 ) for two suppressive myeloid populations, granulocytic MDSCs and tumor associated macrophage type II in addition to the lymphoid populations of cytotoxic CD8+ T-cells and the suppressive regulator T-cells (Tregs). Shown is the percentage of the total CD45+ cells for the population ⁇ SEM. One-way ANOVA pairwise comparison (p ⁇ 0.05).
  • TNO155 and anti-PD1 displayed a robust decrease in the T-cell suppressive population of granulocytic myeloid derived suppressor cells (gMDSCs: Ly6G+, Ly6C+, C11b+, F4/80+), tumor associated macrophages type II (TAMII: Ly6G-, Ly6C+, CD11b+, F4/80+, MHCII-), and an increase in cytotoxic CD8+ T-cells (CD8+: CD45+, CD3+, CD8+) in the tumor.
  • gMDSCs Ly6G+, Ly6C+, C11b+, F4/80+
  • TMII tumor associated macrophages type II
  • CD8+ an increase in cytotoxic CD8+ T-cells
  • CD8+ CD45+, CD3+, CD8+
  • PBMC Peripheral blood mononuclear cells
  • a CellTiter-Glo ® (CTG) cell viability assay was performed according to manufacturer's instructions using a separate plate with identically seeded cells and also performed for all plates after 6 days of incubation with TNO155.
  • the Day 6 measurements were normalized with DMSO treated groups as 100% to evaluate the TNO155 effects on the M-CSF stimulated proliferation of monocytes and the Day 0 cell seeding measurement was indicated by the light dotted line.
  • TNO155 can block the conversion of monocytes in the tumor microenvironment to immune-suppressive macrophages after being exposed to the M-CSF ligands in the tumors and synergizes with PD1 targeting agents that reinvigorate the exhausted T cells in the tumors.
  • the data presented provides in vivo evidence of SHP2's role in immune modulation in the tumor.
  • the presence of the PTPN11-G503V mutation in the MC38 is an excellent tool to examine the effects of TNO155 specifically within the tumor microenvironment.
  • Similar mutations in human SHP2 have been found to exist in JMML and Noonan syndrome patients where activating mutations, such as the G503V mutation, keep the SHP2 protein in an open confirmation and thus preventing the presence of the binding pocket for allosteric binding of TNO155.
  • TNO155 is dosed daily (QD) 2 weeks on/1 week off on a 21-day cycle (starting at 20 mg QD).
  • Spartalizumab is dosed at 300 mg every 3 weeks on a 21-day cycle.
  • CTNO155B12101 patients with advanced EGFR WT, ALK WT, KRAS G12C and KRAS WT NSCLC are studied along with patients with advanced HNSCC (+/- naive to prior immuno-oncologic therapy).
  • Patients are treated with advanced solid tumors (with evaluable disease) fitting into one of the following groups: i). advanced EGFR WT, ALK WT NSCLC, after progression on or intolerance to platinum-containing combination chemotherapy; ii). Advanced HNSCC or esophageal SCC, after progression on or intolerance to platinum-containing combination therapy; iii). Advanced CRC, after progression on or intolerance to standard-of-care (SOC) therapy per local guidelines.
  • SOC standard-of-care

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Claims (13)

  1. Combinaison pharmaceutique comprenant : (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-méthyl-2-oxa-8-azaspiro[4.5]décan-4-amine (TNO155) : ou un sel pharmaceutiquement acceptable de celle-ci,
    et un inhibiteur de point de contrôle immunitaire.
  2. (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyhdin-4-yl)thio)pyrazin-2-yl)-3-méthyl-2-oxa-8-azaspiro[4.5]décan-4-amine (TN0155) : ou un sel pharmaceutiquement acceptable de celle-ci, pour une utilisation dans le traitement du cancer, dans laquelle le traitement comprend en outre l'administration d'un inhibiteur de point de contrôle immunitaire.
  3. Inhibiteur de point de contrôle immunitaire pour une utilisation dans le traitement du cancer, dans lequel le traitement comprend en outre l'administration de (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-méthyl-2-oxa-8-azaspiro[4.5]décan-4-amine (TN0155) : ou d'un sel pharmaceutiquement acceptable de celle-ci.
  4. Combinaison pharmaceutique selon la revendication 1, TNO155 ou sel pharmaceutiquement acceptable de celle-ci pour une utilisation selon la revendication 2, ou inhibiteur de point de contrôle immunitaire pour une utilisation selon la revendication 3, dans laquelle l'inhibiteur de point de contrôle immunitaire est un inhibiteur de PD-1.
  5. Combinaison pharmaceutique selon la revendication 4, TNO155 ou sel pharmaceutiquement acceptable de celle-ci pour une utilisation selon la revendication 4, ou inhibiteur de point de contrôle immunitaire pour une utilisation selon la revendication 4, dans laquelle l'inhibiteur de PD-1 est PDR001, Nivolumab, Pembrolizumab, Pidilizumab, MEDI0680, REGN2810, TSR-042, PF-06801591, BGB-A317, BGB-108, INCSHR1210, ou AMP-224.
  6. Combinaison pharmaceutique selon l'une quelconque des revendications 1, 4 et 5, TNO155 ou sel pharmaceutiquement acceptable pour une utilisation selon l'une quelconque des revendications 2, 4 et 5, ou inhibiteur de point de contrôle immunitaire pour une utilisation selon l'une quelconque des revendications 3 à 5, dans laquelle le TNO155 ou le sel pharmaceutiquement acceptable et l'inhibiteur de point de contrôle immunitaire sont dans des formulations séparées.
  7. Combinaison pharmaceutique selon l'une quelconque des revendications 1 et 4 à 6, pour une utilisation en tant que médicament.
  8. Combinaison pharmaceutique selon l'une quelconque des revendications 1 et 4 à 6, pour une utilisation dans le traitement du cancer.
  9. Combinaison pharmaceutique pour une utilisation selon la revendication 8, TNO155 ou sel pharmaceutiquement acceptable de celle-ci pour une utilisation selon l'une quelconque des revendications 2 et 4 à 6, ou inhibiteur de point de contrôle immunitaire pour une utilisation selon l'une quelconque des revendications 3 à 6, dans laquelle le cancer est choisi parmi le carcinome épidermoïde de l'œsophage, le carcinome épidermoïde de la tête et du cou, le cancer colorectal, le cancer de l'ovaire, le cancer du pancréas, le cancer du poumon non à petites cellules et le carcinome de cellules rénales.
  10. Combinaison pharmaceutique pour une utilisation selon l'une quelconque des revendications 7 à 9, TNO155 ou sel pharmaceutiquement acceptable de celle-ci pour une utilisation selon l'une quelconque des revendications 2, 4 à 6 et 9, ou inhibiteur de point de contrôle immunitaire pour une utilisation selon l'une quelconque des revendications 3 à 6 et 9, dans laquelle le TNO155 ou le sel pharmaceutiquement acceptable et l'inhibiteur de point de contrôle immunitaire sont administrés simultanément, séparément ou sur une période de temps.
  11. Combinaison pharmaceutique selon l'une quelconque des revendications 7 à 10, TNO155 ou sel pharmaceutiquement acceptable de celle-ci pour une utilisation selon l'une quelconque des revendications 2, 4 à 6, 9 et 10, ou inhibiteur de point de contrôle immunitaire pour une utilisation selon l'une quelconque des revendications 3 à 6, 9 et 10, dans laquelle le TNO155 ou le sel pharmaceutiquement acceptable de celle-ci est administré par voie orale à une dose d'environ 1,5 mg par jour, ou 3 mg par jour, ou 6 mg par jour, ou 10 mg par jour, ou 20 mg par jour, ou 30 mg par jour, ou 40 mg par jour, ou 50 mg par jour, ou 60 mg par jour, ou 70 mg par jour, ou 80 mg par jour, ou 90 mg par jour, ou 100 mg par jour.
  12. Combinaison pharmaceutique pour une utilisation selon l'une quelconque des revendications 7 à 11, TNO155 ou sel pharmaceutiquement acceptable de celle-ci pour une utilisation selon l'une quelconque des revendications 2, 4 à 6 et 9 à 11, ou inhibiteur de point de contrôle immunitaire pour une utilisation selon l'une quelconque des revendications 3 à 6 et 9 à 11, dans laquelle la dose de TNO155 par jour est sur un cycle de 21 jours de 2 semaines sur un médicament suivi d'1 semaine sans médicament.
  13. Combinaison pharmaceutique pour une utilisation selon l'une quelconque des revendications 7 à 12, TNO155 ou sel pharmaceutiquement acceptable de celle-ci pour une utilisation selon l'une quelconque des revendications 2, 4 à 6 et 9 à 12, ou inhibiteur de point de contrôle immunitaire pour une utilisation selon l'une quelconque des revendications 3 à 6 et 9 à 12, dans laquelle l'inhibiteur de point de contrôle immunitaire est administré par voie intraveineuse.
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